The objective of this proposal is to define the mechanisms mediating hypertension in a model of pregnancy-induced hypertension produced by chronic reduction in uterine perfusion pressure in pregnant rats. The central hypothesis to be tested in this proposal is that a reduction in uteroplacental perfusion pressure causes hypertension by reducing renal-pressure natriuresis. The reduction in pressure natriuresis occurs as a result of tumor necrosis factor causing endothelial cell activation that leads to enhanced formation of endothelin. These abnormalities reduce renal plasma flow and glomerular filtration thereby decreasing renal sodium excretory function. To test this hypothesis, arterial pressure, renal and endothelial function will be examined in a conscious, chronically instrumented rat model of chronic PIH produced by long-term reduction in uterine perfusion pressure. Specific aims to be addressed are: 1) To test the hypothesis that abnormalities in cardiovascular and renal function during chronic reductions in uteroplacental perfusion pressure are due to elevations in maternal plasma TNF alpha; 2) To test the hypothesis that endothelin plays an important role in mediating TNF alpha-induced abnormalities in cardiovascular and renal function in pregnant rats; 3) To test the hypothesis that estrogens and/or progesterone enhance the endothelial activation and hypertensive response to TNF alpha.